Marie-Dominique Filippi, PhD

Use of hematopoietic stem cells (HSCs) for clinical transplantation is something occurring for decades. HSCs have the unique ability to give rise to all mature immune and blood cell lineages while at the same time regenerating themselves in a process named “self-renewal” to meet the bone marrow regenerative needs and sustain hematopoiesis. Yet for quite sometime we knew that the functionality of HSCs declines after high demand in blood cell regeneration, such that after hematopoietic cell transplant, HSCs can fail to adequately respond to subsequent regenerative needs. In our study, we uncovered a fundamental mechanism behind the functional decline of HSC after bone marrow transplantation. Using mouse models of bone marrow transplantation, we found that the mitochondria of HSC undergo major remodeling during bone marrow regeneration. This remodeling is irreversible and passes on to the HSC progeny via asymmetric division. Mitochondrial remodeling alters the coordinated regulation of cell cycle and metabolism, which decreases HSC regeneration capacity. This irreversible mitochondrial remodeling likely serves as the biological memory of adult stem cells to protect against uncontrolled HSC expansion. Although this biological memory of HSC may help prevent overgrowth and leukemia development, it hampered the outcomes of HSC functions under bone marrow transplantation conditions. Our data provides fundamental insights into what goes awry during bone marrow transplant. Restoring some of mitochondrial functions in HSCs will help improve HSC functions after bone marrow transplantation.